LoDoCo2

2016

The aim of the LoDoCo2 (Low Dose Colchicine for secondary prevention of cardiovascular disease) trial was to investigate the effect of low dose colchicine (0,5 mg once daily) on the risk of myocardial infarction (fatal or non-fatal), stroke, or the need for coronary bypass or stent placement. While the precise mechanism through which colchicine mitigates major cardiovascular events remains incompletely understood, it is hypothesized that its anti-inflammatory effects contribute to risk reduction among patients with established atherosclerotic disease.

LoDoCo2 stands out in several respects. It represents a large-scale randomized clinical trial conducted entirely by a non-academic network of cardiologists and a consortium of pharmaceutical companies with a focus on drug repurposing. This trial underscores the potential value of older, often cost-effective medications in advancing the development of new innovative drugs.

The Research
Following a median follow-up period of 3 years, the addition of colchicine to standard treatment resulted in a 30% reduction in risk of myocardial infarction (fatal or non-fatal), stroke, or the need for coronary bypass or stent placement. Patients treated with colchicine exhibited similar side effects compared to those receiving a placebo. Furthermore, no interactions were found with other commonly used drugs such as (potent) statins.

In 2021, certain international guidelines had already incorporated colchicine into the secondary prevention of atherosclerotic cardiovascular disease (ASCVD). Subsequently, in 2023, the Food and Drug Administration (FDA) approved Lodoco® (colchicine) for reducing the risk of myocardial infarction (MI), stroke, coronary revascularization, and cardiovascular (CV) death in adult patients with established atherosclerotic disease or multiple risk factors for CV disease. This approval was based on published data regarding the effects of colchicine on cardiovascular events, along with insights from the LoDoCo2 trial. The LoDoCo2 investigators anticipate that colchicine will become the standard treatment for patients with coronary artery disease.

The origin

The LoDoCo2 trial is based on based on LoDoCo, a small Australian trial that assessed the benefits of administration of a low dosis colchicine on coronary artery disease (CAD). Colchicine is a relatively inexpensive medication commonly used for the treatment of inflammatory disease, e.g. gout. The LoDoCo2 trial was executed with a similar protocol in Australia and the Netherlands.

LoDoCo2 is special in many ways; it is a large randomised clinical trial fully run by a non-academic network of cardiologists (WCN), funded by The Dutch Heart Foundation and ZonMw (Goed Gebruik Geneesmiddelen) and a consortium of pharmaceutical companies with focus on drug repurposing. Although the recruitment of patients already started before the start of the DCVA, the DCVA always has provided strong support, also in the route towards implementation. This drug-repurposing clinical trial shows that a collaborative statement from the DCVA and its partners is needed to change rules and regulations in order to make this effective, safe and cheap old treatment available for patients.

Collaborators

Funded

Contact person:

A. Schut (Astrid)

a.schut@wcn.life

Principal investigators

Dr. A. Mosterd (Arend)

Prof. Dr. J.H. Cornel (Jan Hein)

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Atrial fibrillation and heart failure are two of the major cardiovascular challenges of our time. It is important that these conditions are detected in time and treated according to guidelines. This is far from always the case. It is sometimes not clear that certain symptoms are caused by atrial fibrillation or heart failure, neither to the patient himself nor to health care providers. As a result, it sometimes takes a long time before someone receives the right treatment.
The chronic nature of heart diseases such as atrial fibrillation and heart failure also means that patients with these conditions are seen by many healthcare providers. To achieve this in a high-quality and transparent manner, optimal cooperation between the various care domains is necessary. It is important that the principle of right care in the right place (JZOJP) is applied. However, network care is complex and the effective organization of JZOJP by the right healthcare professional is still far from commonplace despite the many initiatives.
The origin
Better treatment of these conditions was a priority on the cardiovascular disease research agenda. This is why the Dutch Heart Foundation and ZonMw have started the thematic collaboration “Right Heart Care In the Right Place". By combining expertise, we want to detect as many people as possible with atrial fibrillation and heart failure early and treat them optimally. We are doing this in various ways: jointly setting up subsidy rounds to support regional collaborations, supporting a national support structure for the regions and overarching activities that contribute to knowledge development.
As part of Right Heart Care In the Right Place, the network program of the Dutch Society of Cardiology, NVVC Connect, together with involved network partners, facilitates an adequate national support structure for affiliated regional collaborations, or Connect regions. The Connect regions are supported and guided in, for example, preparing the subsidy application and they receive support during the implementation of the regional transmural agreements.
The research
The Right Heart Care In the Right Place consists of two forms of support:

the National Impulse: the aim is to set up a sustainable national support structure that stimulates and guides regions in the regional design and implementation of network care in the field of atrial fibrillation and heart failure
the Regional Impulse: the aim of the Regio-Impulse Cardiac Care is to support regional alliances, the Connect regions, in implementing regional transmural agreements. By bringing together the various care providers from the 3rd, 2nd and 1st line, these collaborative ventures jointly offer cardiological care for atrial fibrillation or heart failure more integrally and transmurally. In this way, the patient comes into contact with the healthcare provider who can best contribute to the care need at that moment. A maximum of 22 Connect regions can receive funding to implement the transmural agreements or to optimize the implementation in their region.

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DECISION

2020

Digoxin is the oldest, market-authorized drug for heart failure (HF), and very cheap. A large trial with digoxin, the DIG trial, executed in the early nineties revealed a highly significant reduction in HF hospitalizations, but no effect on mortality. A post-hoc analysis of the DIG trial suggests that low serum concentrations of digoxin may not only improve HF hospitalizations but also mortality in chronic HF patients. To validate these findings, a prospective, randomized, placebo-controlled trial is required to redefine the role of digoxin in modern HF treatment.
The Focus
The primary objective of this study is to investigate whether low-level digoxin (targeting serum concentrations of 0.5-0.9 ng/mL), compared to a placebo, reduces (repeated) HF hospitalizations, (repeated) urgent HF hospital visits, and cardiovascular mortality when added to standard guideline-recommended therapies in chronic HF patients with reduced or mid-range ejection fractions (LVEF ≤50%).
The Research
This proposed trial is a national, multicenter, randomized, double-blind, placebo-controlled clinical trial involving 982 chronic HF patients aged ≥18 years, classified as NYHA II to ambulatory IV, LVEF ≤50%, and specific serum NT-proBNP concentrations based on rhythm and recent HF hospitalization status. Patients must also be on guideline-recommended therapies. The study population includes at least one-third with atrial fibrillation (AF) and one-third women to represent the real-life HF population.
Patients were randomized to receive either a low-level digoxin or a placebo in a double-blinded manner. Digoxin Teva will be administered orally, starting at doses of 0.2mg or 0.1mg (based on age, renal function, and concomitant medication). No loading dose is given to the placebo group. After 4 weeks of evaluating medication (digoxin or placebo), concentrations will be measured. Dose adjustments will be made if needed to reach the target serum digoxin concentration range of 0.5-0.9ng/mL.
The outcomes in reducing adverse cardiovascular events in patients with chronic heart failure of low-dose digoxin will be compared to the outcomes of the placebo.
The origin
This study was funded as part of the Dutch Heart Foundation's collaboration with the ZonMw GGG program on Good Use of Medicines (Goed Gebruik Geneesmiddelen) for better treatment of heart failure and atrial fibrillation, which was one of the 5 priority's that the Dutch Heart Foundation set in 2014. The DECISION study involves 38 hospitals and is led by cardiologists from UMC Groningen and the WCN.

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